Helen T. Chifotides

Anion-π interactions in supramolecular architectures.

The study of the noncovalent force between π-acidic aromatic systems and anions, referred to as the anion-π interaction, has recently emerged as a new branch of supramolecular chemistry. The anion-π contact is complementary to the cation-π interaction, a prominent noncovalent force involved in protein structure and enzyme function. Until recently, the scientific community had overlooked the anion-π interaction due to its ostensibly counterintuitive nature. Pioneering theoretical studies in 2002, however, established that anion-π interactions are energetically favorable (~20-70 kJ/mol) and prompted a flurry of reports in support of their existence. The interest in anion-π contacts was further fueled by the importance of anions in key chemical and biological processes and the involvement of π-rings in anion recognition and transport. Anion-π interactions hold great promise for the design of selective anion receptors, hosts or scaffolds, colorimetric sensors, and catalysts and may also affect biological functions. Currently, the area of anion-π research is highly topical in the scientific community and on a meteoric rise in the chemical literature. This Account highlights our leading findings in this burgeoning area. Our work has focused on comprehensive investigations of several unprecedented supramolecular systems, in which the anions and their close anion-π contacts are the driving elements of the final architectures. We surveyed several heterocyclic π-acidic aromatic systems amenable to anion-π contacts and explored the subtle interplay between ligand π-acidity, anion identity, and metal ions in mediating the ensuing self-assembled architectures. The reactions we performed between solvated first-row transition metal ions and the π-acidic ligands bptz (3,6-bis(2-pyridyl)-1,2,4,5-tetrazine) or bmtz (3,6-bis(2-pyrimidyl)-1,2,4,5-tetrazine) resulted in unprecedented metallacycles. Our investigations revealed that the identity of the encapsulated ion dictates the metallacycle nuclearity and close anion-π contacts are critical for the metallacycle stability. Our X-ray crystallographic, NMR spectroscopic, and mass spectrometric (MS) studies demonstrated that the tetrahedral ([BF4](-), [ClO4](-)) and octahedral ([SbF6](-), [AsF6](-), [PF6](-)) anions template discrete molecular squares and pentagons, respectively. The metal ions occupy the vertices, and bptz or bmtz moieties span the edges of the metallacycles. The encapsulated anions occupy the π-acidic cavities of the metallacycles and establish multiple close directional F/O···C(tetrazine) contacts with the edges. The observation of notable (19)F solid-state NMR chemical shifts reflects the short contacts of the encapsulated anions, findings that we corroborated by DFT calculations. The solution NMR data support the conclusion that bona fide metallacycle templation and interconversion between the metallacycles in solution occurs only in the presence of the appropriate anions. The NMR, MS, and CV data underscore the remarkable metallapentacycle stability despite the angle strain inherent in pentagons formed by octahedral metal ions. The low anion activation energies of encapsulation (ΔG(‡) ~ 50 kJ/mol) suggest that anion-π contacts assist the anion templation. We also studied reactions of Ag(I)X (X(-) = [PF6](-), [AsF6](-), [SbF6](-), [BF4](-)) with bptz or bppn (3,6-bis(2-pyridyl)-1,2-pyridazine) to assess the effect of the ligand π-acidity on the preferred structures. The X-ray data revealed that the higher π-acidity of the tetrazine ring in bptz leads to propeller-type products [Ag2(bptz)3](2+) exhibiting prominent short anion-π contacts. By contrast, the less π-acidic bppn preferentially favors grids [Ag4(bppn)4](4+) which exhibit maximized π-π interactions. Finally, we explored the reactions of the extended π-acidic heterocycle HAT(CN)6 (1,4,5,8,9,12-hexaazatriphenylene-hexacarbonitrile) with the Cl(-), Br(-), I(-) ions which lead to highly colored solutions/crystals. X-ray crystallographic studies of the HAT(CN)6/halide complexes revealed unprecedented multisite short peripheral charge-transfer and centroid anion-π contacts. In solution, the charge-transfer contacts were evidenced by electronic absorption, (13)C and halogen NMR, as well as MS data. The distinctly colored complex entities exhibit extraordinarily high association constants, which render them promising for anion-sensing receptor applications.

Supramolecular architectures with π-acidic 3,6-bis(2-pyridyl)-1,2,4,5-tetrazine cavities: role of anion-π interactions in the remarkable stability of Fe(II) metallacycles in solution.

The comprehensive investigation reported herein provides compelling evidence that anion-π interactions are the main driving force in the formation of self-assembled Fe(II)-templated metallacycles with bptz [3,6-bis(2-pyridyl)-1,2,4,5-tetrazine] in high yields. It was demonstrated by X-ray crystallography, (1)H NMR, solution and solid-state MAS (19)F NMR spectroscopies, CV and MS studies that the anions [X](-) = [BF(4)](-), [ClO(4)](-) and the anions [Y](-) = [SbF(6)](-), [AsF(6)](-), [PF(6)](-) template molecular squares [Fe(4)(bptz)(4)(CH(3)CN)(8)][X](8) and pentagons [Fe(5)(bptz)(5)(CH(3)CN)(10)][Y](10), respectively. The X-ray structures of [{Fe(4)(bptz)(4)(CH(3)CN)(8)}⊂BF(4)][BF(4)](7) and [{Fe(5)(bptz)(5)(CH(3)CN)(10)}⊂2SbF(6)][SbF(6)](8) revealed that the [BF(4)](-) and [SbF(6)](-) anions occupy the π-acidic cavities, establishing close directional F···C(tetrazine) contacts with the tetrazine rings that are by ~0.4 Å shorter than the sum of the F···C van der Waals radii (ΣR(vdW) F···C = 3.17 Å). The number and strength of F···C(tetrazine) contacts are maximized; the F···C(tetrazine) distances and anion positioning versus the polygon opposing tetrazine rings are in agreement with DFT calculations for C(2)N(4)R(2)···[X](-)···C(2)N(4)R(2) (R = F, CN; [X](-) = [BF(4)](-), [PF(6)](-)). In unprecedented solid-state (19)F MAS NMR studies, the templating anions, engaged in anion-π interactions in the solid state, exhibit downfield chemical shifts Δδ((19)F) ≈ 3.5-4.0 ppm versus peripheral anions. NMR, CV, and MS studies also establish that the Fe(II) metallacycles remain intact in solution. Additionally, interconversion studies between the Fe(II) metallacycles in solution, monitored by (1)H NMR spectroscopy, underscore the remarkable stability of the metallapentacycles [Fe(5)(bptz)(5)(CH(3)CN)(10)][PF(6)](10) ≪ [Fe(5)(bptz)(5)(CH(3)CN)(10)][SbF(6)](10) < [Fe(5)(bptz)(5)(CH(3)CN)(10)][AsF(6)](10) versus [Fe(4)(bptz)(4)(CH(3)CN)(8)][BF(4)](8), given the inherent angle strain in five-membered rings. Finally, the low anion activation energies of encapsulation (ΔG(‡) ≈ 50 kJ/mol), determined from variable-temperature (19)F NMR studies for [Fe(5)(bptz)(5)(CH(3)CN)(10)][PF(6)](10) and [Zn(4)(bptz)(4)(CH(3)CN)(8)][BF(4)](8), confirm anion encapsulation in the π-acidic cavities by anion-π contacts (~20-70 kJ/mol).

Lanthanide–3d cyanometalate chains Ln(III)–M(III) (Ln = Pr, Nd, Sm, Eu, Gd, Tb; M = Fe) with the tridentate ligand 2,4,6-tri(2-pyridyl)-1,3,5-triazine (tptz): evidence of ferromagnetic interactions for the Sm(III)–M(III) compounds (M = Fe, Cr)

A series of cyanide-bridged chain mixed Fe(III)/Ln(III) (Ln=Pr, Nd, Sm, Eu, Gd, Tb) complexes with the tridentate ligand 2,4,6-tri(2-pyridyl)-1,3,5-triazine (tptz) used as a capping group has been prepared. Reactions of tptz and LnCl3 with K3Fe(CN)6 yield a family of air-stable 1-D compounds {[Pr(tptz)(H2O)4Fe(CN)6].8H2O}infinity, {[Nd(tptz)(H2O)4Fe(CN)6].8H2O}infinity, {[Sm(tptz)(H2O)4Fe(CN)6].8H2O}, {[Eu(tptz)(H2O)4Fe(CN)6].6H2O}infinity, {[Gd(tptz)(H2O)4Fe(CN)6].6H2O}infinity, and {[Tb(tptz)(H2O)4Fe(CN)6].8H2O}infinity. Temperature dependent magnetic susceptibility studies of reveal that in , the Sm(III) and Fe(III) ions are ferromagnetically coupled with 3-D ordering occurring below 3.5 K. The appearance of the frequency dependent out-of-phase signal is explained in terms of an ordering with a spin glass-like behavior. To compare the magnetic behavior of with related compounds, {[Sm(tptz)(H2O)4Co(CN)6].8H2O}infinity and {[La(tptz)(DMF)(H2O)3Fe(CN)6].5H2O}infinity, {[Sm(tmphen)(DMF)3(H2O)Fe(CN)6].2H2O}infinity, {[Sm(tmphen)2(H2O)2Fe(CN)6].MeOH.13H2O}infinity and {[Sm(tmphen)2(H2O)2Cr(CN)6].MeOH.9H2O}infinity with 3,4,7,8-tetramethyl-1,10-phenanthroline (tmphen) were also prepared.

Anion-pi interactions.

This tutorial review provides an overview of the theoretical and experimental investigations that resulted in the recognition of anion-pi interactions, i.e., non-covalent forces between electron deficient aromatic systems and anions. Several pioneering theoretical studies revealed that these interactions are energetically favorable (approximately 20-50 kJ mol(-1)). Anion-pi interactions are gaining significant recognition, and their pivotal role in many key chemical and biological processes is being increasingly appreciated. The design of highly selective anion receptors and channels represent important advances in this nascent field of supramolecular chemistry.

Structural evidence for monodentate binding of guanine to the dirhodium(II,II) core in a manner akin to that of cisplatin

The reaction of Rh2(OAc)4(bpy) (bpy = 2,2′-bipyridine) with 9-ethylguanine (9-EtGH) proceeds with substitution of two acetate ligands to produce [Rh2(OAc)2(bpy)(9-EtGH)(H2O)2(CH3SO4)][CH3SO4]·(H2O) (1), which has been structurally characterized. In compound 1, the equatorial sites of one rhodium center are occupied by a chelating bpy molecule and 9-EtGH is equatorially coordinated via N(7) to the other rhodium center. The interaction of the 9-EtGH base with the dirhodium core is further stabilized by an intramolecular hydrogen bond between the purine O(6) and the equatorial water molecule. The eight non-equivalent bpy proton resonances, as well as that of the purine H(8) (which shifts upfield upon coordination as compared to free 9-EtGH, due to bpy ring current effects), were assigned by means of 2D NMR spectroscopy. The pH titration curve of the H(8) proton reveals pH-independent behavior and a pKa value of 8.0 for N1–H deprotonation; both observations corroborate N(7) binding of the purine base to the dirhodium unit in solution. These findings indicate that, in the presence of a chelating agent that blocks one rhodium center, 9-EtGH binds to a single rhodium center in a monodentate fashion via N(7), instead of in a bridging fashion through the N(7) and O(6) sites as previously noted.

Synthesis, X-ray structure, interactions with DNA, remarkable in vivo tumor growth suppression and nephroprotective activity of cis-tetrachloro-dipivalato dirhenium(III).

In this study we report the synthesis, the X-ray crystal structure and the in vivo tumor growth suppression and nephroprotective activity of bis-dimethylsulfoxide-cis-tetrachlorodi-μ-pivalatodirhenium(III), cis-Re2[(CH3)3CCOO]2Cl4·2(CH3)2SO (I). The interactions of I with DNA were also investigated by electrophoretic mobility shift assays, electronic absorption titrations, ΔTm and viscosity measurements, which indicate that compound I interacts relatively strongly with the DNA (Kb 2.2×10(3)M(-1)), most likely by forming covalent interstrand cross-links, and by kinking and unwinding supercoiled DNA; moreover, DNA cleavage by I is enhanced in the presence of redox-active species. The in vivo antitumor activity of I is considerable and is accompanied by significant elimination of red blood cell and kidney damage. Remarkably, compound I in combination with cisplatin (combined Re-Pt antitumor system) led to suppression of tumor growth or complete tumor elimination. The antihemolytic and nephroprotective abilities of I only or as a part of the Re-Pt antitumor system were established and a possible mechanism for the influence of I on these properties, involving erythropoietin production, is proposed.

Synthesis, spectroscopic and magnetic resonance studies of mercury(II) and methylmercury(II) complexes of azathioprine, a biologically active mercaptopurine derivative

Synthetic and spectroscopic studies of the Hg(II) and MeHg(II) complexes of azathioprine (AZA), a biologically active 6-mercaptopurine derivative, were undertaken. The altered coordination behavior of AZA with respect to the parent mercaptopurine, with sulfur no longer being the primary donor atom, was confirmed. As concluded by the 1H NMR, 13C NMR, and IR spectroscopic data, Hg(II) binds to the N(9) position of deprotonated AZA, while in the MeHg(II) compound, coordination occurs through the N(3) and N(9) positions of the purine ring. The values of the coupling constants 2J (199Hg-1H), 1J(199Hg-13C) for the MeHg(II) compound further support complexation via nitrogen atoms of the purine. Elemental analyses confirmed the compounds to be Hg(AZA)2 (1) and [(MeHg)2(AZA)](NO3) (2); conductivity measurement values show that 1 is a nonelectrolyte and 2 is a 1:1 electrolyte. Furthermore, the FAB-MS of the compounds confirms direct binding of the metal to the ligand, and in the case of the MeHg(II) compound, the successive loss of one and two MeHg(II) moieties can be clearly observed.

Unprecedented partial paddlewheel dirhodium methyl isocyanide compounds with unusual structural and electronic properties: a comprehensive experimental and theoretical study

A series of dirhodium acetonitrile compounds, namely cis-[Rh2(DTolF)2(CH3CN)6][BF4]2 (1) cis-[Rh2(F-form)2(CH3CN)6][BF4]2 (2), cis-[Rh2(NNN)2(CH3CN)6][BF4]2 (3) ([F-form]−: p-difluorophenylformamidinate, [NNN]−: p-ditolyltriazenide, [DTolF]−: p-ditolylformamidinate), cis-[Rh2[Ph2P(C6H4)]2(CH3CN)6][BF4]2 (4) and their unprecedented methyl isocyanide analogs 5–8, respectively, were synthesized and characterized by X-ray crystallography, cyclic voltammetry, NMR, electronic and infrared spectroscopies. The elongation of the Rh–Rh distances (∼0.07 A) and the bonds trans to eq CH3NC in 5–8vs.1–4 are in accord with the strong trans influence of isocyanide. The short Rh–C (CH3NC) distances in 5–8 are attributed to π-backbonding, whereas the short CN distances in CH3NC and the high energy ν(CN) stretches are attributed to appreciable σ-donation of CH3NC. Of particular note are the longer Rh–Rh bonds (∼2.76 A) that 8 exhibits and unprecedented short ax Rh–C distances in the same range as the eq Rh–C bonds (2.01–2.04 A) for CH3NC. TD-DFT calculations predict the lowest-energy LMCT transitions in the order 1 < 2 < 5 < 6, 3 < 7 and the HOMO–LUMO energy gaps to be greater in 5–7vs.1–3, respectively, findings corroborated by electrochemical and electronic spectral data. This trend is attributed to the stabilization of the HOMOs and destabilization of the LUMOs in 5–7. The π-backbonding in 5–8 stabilizes the Rh2(π*) orbitals and σ-donation from CH3NC destabilizes the Rh2(σ) orbitals, with the extreme case being 8 where Rh2(σ) becomes the HOMO. This fact accounts for the ∼20-fold increase in intensity of the HOMO Rh2(σ) → LUMO Rh2(σ*) transition for 8 (∼370 nm) vs.4, also in accord with TD-DFT calculations.

Complexes of azathioprine, a biologically active mercaptopurine derivative, with Pt(II), Pd(II), Rh(III), Ru(III) and Ag(I).

In order to possibly elucidate the prevailing factors determining the binding sites in the interactions of azathioprine (AZAH), a biologically active 6-mercaptopurine derivative, with the platinum group and other heavy metals, we probed the binding sites of AZAH with Pt(II), Pd(II), Rh(III), Ru(III), and Ag(I) by using 1H and 195Pt NMR, ESR, and IR spectroscopic techniques as well as magnetic susceptibility measurements and mass spectrometry. The altered coordination behavior of AZAH with respect to the parent 6-mercaptopurine, with sulfur no longer being the primary binding site, was ascertained. In the Pt(II), Rh(III), and Ru(III) complexes, 1H NMR data imply coordination of the metal through the N(3) and N(9) positions of the purine ring, while in the case of the Pt(II) compound, 195Pt NMR data further ascertain AZAH binding in a bridging mode through ring nitrogens. As opposed to the aforementioned metals, in the Pd(II) and Ag(I) compounds, 1H NMR data suggest binding via the N(9) position of deprotonated AZAH. Conductivity measurements for all compounds, except for that of Pt(II), showed a nonelectrolyte behavior in solution; the presence of ionic nitrate in the Pt(II) compound was further ascertained by IR spectroscopy. The coordination sphere of the metal in the cases of the Pt(II) and Pd(II) compounds is completed by ammonia and water molecules, respectively, while in those of the Rh(III) and Ru(III) compounds is completed by chloride bridge. For the Ru(III) compound, the latter is confirmed by magnetic susceptibility measurements.

Synthesis and X-ray crystal structure of the dirhenium complex Re2(i-C3H7COO)4Cl2 and its interactions with the DNA purine nucleobases.

The dirhenium complex Re2(i-C3H7COO)4Cl2 was synthesized and characterized by X-ray crystallography, (1)H NMR and electronic spectroscopies, and electrospray ionization-mass spectrometry. The reactions of Re2(i-C3H7COO)4Cl2 with the substituted DNA purine nucleobases guanine (9-methylguanine and 9-ethylguanine) and adenine (9-methyladenine and 9-ethyladenine) were investigated by proton nuclear magnetic resonance and electronic spectroscopies as well as electrospray ionization-mass spectrometry. The data corroborate binding of two 9-methylguanine (or 9-ethylguanine) and 9-methyladenine (or 9-ethyladenine) bases per dirhenium unit in a bidentate fashion, in equatorial positions, via sites N7/O6 and N1/N6, respectively, with concomitant substitution of two carboxylate groups to form a single isomer of cis-Re2(i-C3H7COO)2(nucleobase)2Cl2. The binding of the bases to the dirhenium core disrupts important nucleobase interactions and may have important biological implications with respect to the anticancer activity of dirhenium complexes.